Recent genome wide association studies (GWAS) have provided increased insight into the genetic basis of complex cardio-metabolic diseases (CMD) including type-2 diabetes and atherosclerotic cardiovascular diseases. Such discoveries, however, only explain a small proportion of the heritability suggesting genetic influences other than common DNA variation need to be considered. Knowledge of the transcriptome is essential for a more complete understanding of the inherited functional elements of the genome. The advent of high-throughput RNA sequencing (RNA-seq), including our work, demonstrates the existence of a far greater transcriptomic complexity and diversity than previously catalogued. The host response to endotoxin (LPS) provides fundamental insights into transcriptomic regulation of innate immunity while also serving as a model for inflammatory CMD. In the Genetics of Evoked-Responses to Niacin and Endotoxemia (GENE) study, we recruited healthy individuals (N=286) to an inpatient protocol and collected blood and adipose samples before and after administration of endotoxin (1ng/kg intravenously). Here, we propose to perform monocyte and adipose transcriptomic and epigenomic profiling during experimental human endotoxemia in order to discover tissue-specific mechanisms of human disease. In Aim 1, we will utilize the clinical-inflammatory response in GENE participants to identify extreme low (~<5%PC) and high (~>95%PC) responders in order to detect endotoxin-induced transcriptomic responses of greatest clinical relevance. In Aim 2, we will replicate LPS- induced transcriptomic changes, define the epigenetic regulation, and pursue clinical translation of replicated findings. In Aim 3, we hypothesize that basal and endotoxin-evoked epigenome/transcriptome response in differentiated human induced pluripotent stem cells (hiPSC) from GENE participants will resemble that in primary cells and tissues. This proposal combines unique clinical resources, tissue-specific transcriptomics, and ex vivo profiling of hiPSC in order to identify heritable contribution to CMD, discover novel disease mechanisms and therapeutic opportunities, and advance innovation in the study of human disease.